Method and resulting compound from admixing sodium morrhuate and quinine solutions



Patented June 30, 1936 UNITED STATES PATENT OFFICE FROM ADMIXING SODIUM MORRHUATE AND QUININE SOLUTIONS Frederick R. Greenbaum, Philadelphia, Pa.

No Drawing. Application April 18, 1935, Serial No. 17,059

6 Claims.

The object of this invention is to provide a satisfactory clear stable solution of sodium morrhuate and quinine under commercial conditions, such mixture being free from any precipitate, and to provide an improved process for mixing said substances, this application being a continuation in part of Serial No. 722,401, filed April 25, 1934.

A further and more specific object is to provide a product comprising the mixture of sodium morrhuate and quinine. Benzyl alcohol may be used as a local anesthetic and preservative.

A further object is to provide a modified process, which results in a slightly modified product, comprising the combination of sodium morrhuate, quinine alkaloid and normal sodium hydroxide.

It is well known that in the obliterative treatment of varicose veins by means of injections, the solutions that have been used until my work upon the subject have been sodium morrhuate, and quinine urea hydrochloride, or quinine-urethane, in each case such specifics being used singly and 1 independently. Of these, quinine urea hydrochloride and quinine-urethane are water-soluble salts, either hydrochloride or sulphate, and are not the free alkaloid. Therefore, as many patients are quinine idiosyncratic, the use of quinine solutions has frequently heretofore not been permissible, altho the thrombosis or obliteration where quinine solutions can be used is firmer and more resistant than with sodium morrhuate.

On the other hand, many patients will not obliterate with five percent (5%) or even ten percent sodium morrhuate, nor do they respond at all to quinine solutions, aside from the question of idiosyncrasy. Consequently, there has long been a definite need for a solution in which might be combined the advantages of both of these substances, but free from the disadvantages of either as related to any particular type of patients, or in other words a solution which would be completely effective with consistent uniformity, with all patients and it is such a solution that has been devised and is hereinafter described in detail.

Extensive clinical experience, with this combined sodium morrhuate and quinine in five percent (5%) and ten percent (10%) solutions, proves that the addition of a proper amountof quinine alkaloid markedly increases the obliterative action of sodium morrhuate. The presence of sodium morrhuate in combination with the quinine alkaloid appears to eliminate the quinine idiosyncrasy experienced with many patients, permitting a firmer and more resistant sclerosis than that produced by quinine salts or by sodium morrhuate used separately.

Various authorities in the treatment of varicose veins report the combined solution of sodium morrhuate and quinine alkaloid is markedly superior 5 to either of these substances employed singly, by giving a much higher percentage of uniformly desirable results, than can be obtained from the use of sodium morrhuate or quinine salts solutions used individually. In fact, very few unfavorable 10 reactions have been reported to date.

The two substances applied in the same solution are effective as sclerosing agents, and as a result of their combination have the advantage of (a) producing positive and firm sclerosis, (b) 15 rarely producing cramps even to the slightest degree, (c) causing no pain whatsoever, (d) requiring but relatively small dosage, (e) being characterized by low viscosity, (f) being non-toxic, and (g) causing no slough when extravasation occurs, 0 while (h) reactions caused by sodium morrhuate or any quinine appear to be negative or at most slight. Following within a few minutes after injection is made, the vein begins to harden and such hardening usually extends from two to 25 four inches below the point of injection, depending upon the quantity used, the size of the vein, and the individual susceptibility of the particular vein to the treatment. Within twenty-four hours the vein usually becomes hard and firm.

At first, in endeavoring to produce a solution of sodium morrhuate and quinine urethane or quinine urea hydrochloride, I realized that chemically it was considered an impossibility, as in these latter substances quinine hydrochloride is 35 used, and as a result of the acid reaction of each of the salts (quinine urethane and quinine urea hydrochloride), a portion of the sodium morrhuate is neutralized, thereby precipitating the fatty acids of the latter, and producing a cloudy solu- 40 tion which is unfit for clinical use. As it was therefore evident that a novel method of combining the two substances had to be developed, I resorted to quinine alkaloid, which being of a relatively weak basic nature is compatible with, and 45 will very slowly dissolve to the extent of about two percent (2%) in, a hot five to ten percent (5%-l0%) solution of sodium morrhuate, the quinine alkaloid being even less soluble in said solution when cold. 5

This method of mixing the quinine alkaloid with the sodium morrhuate, however, is far too slow for commercial purposes, besides the fact that while the quinine alkaloid is retained in solution, the free alkaloid may be precipitated, thereby making the resulting solution unsuited for clinical use. Consequently, two methods have been devised for satisfactorily dissolving and combining the quinine alkaloid and the sodiiim morrhuate inla resulting clear and table soiution. The first of these processes comprises the dissoi j 'ng of both ofsaid substances in heated benzyl alcohol, which latter substance contributes anesthetic characteristics to: the resulting solution. I

By way of example, the desired solution is obtained by thisprocess, by dissolving, twenty grams (20 grs.), of free alkaloid quinine in twentycubic centimeters (20 cc.) of heated benzyl alcohol, after which this solution is added slowly and with constant stirring to one thousand cubic centimeters (1000 cc.) of a five percent (5%) aqueoussolution of sodium morrhuate; heated andmain'e tained close to the boiling point. Gradually the alkaloid quinine and benzyl alcohol solution becomes dissolved in. the; sodium morrhuatesolution, during the steady' addition of one to; the other. and with constant mechanical, stirring. Finally, a clear solutiorrisobtained, which contains-between five percent 5%) and ten percent- '(10%) of sodium morrhuate, two percent (2%) alkaloid quinine, ands two percent (2% benzyl ,al- (101101;. 7 I V 7,

Having produced the new" mixture thus described, the benzyl: alcohol may be then or at any ..time hereafter distilled off, so as to leave an: equally clear mixture-of the sodium morrhuate and; quinine alkaloid alone, both for use as a simpile mixturejwhere such is desired, or as a commercial: basis for still other mixtures and/or compoundstwithi-onemore still further substances,

depending upon what ultimate preparation or. result is desired.

The. other method hereinbefore ferred. to, and which: is now preferred over. one just described, comprisestheaddition of quinine alkaloidto free fatty acids ofJcod liver oilwhil'eheated, it having. been foundthat the former-is readily. soluble in the latter, and that the former also remains in the oily'solutionf. even after cooling,

andv totally without'the slightesttendency to precipitate; Benzyl alcohol is'then preferably added;.not asasolvent as in the'i'irst-described process, but. for itsanesthetic'and preseryativefunc- I tion, altho theproduct may be made without the addition of benzyl-aieohol, so that its presence in formed, and-when Water is added to'the quinine morrhuateno separation or precipitation of the quinine: alkaloid occurs. clear solution, it isnecessary to add normal sodi umi'hydroxide, by heating and stirring. When the-pHvalue of: the resulting solution is between- 8 and 10, a clear,- stable solution is-obtained,con-- taining five'percent (5%) sodium morrhuate or six" percent (6%), two percent (2%) alkaloidal quinine, and two. percent (21%) 'benzyl alcohol. The sodium. hydroxide performs'the function of transforming the. quinine morrhuate into sodium morrhuate and quinine. Alkaloidai quinine is not. soluble. in an. alkaline :solution; but in. this process of preparing. the quinine morrhuate, it remains -.in. colloidal solution, due to the .dispersoid action of isodium morrhuate (cod liver oil'soap) and possesses the property of: holding in alkaline In, order to obtain a' nine alkaloid; and sodium salts of thefatty .acid

' complexes and. then dissolving the quinine fatty solution such substances as are otherwise insoluble therein.

Ordinarily in making quinine solutions' acid salts are used because quinine is only soluble in Water in acid condition. Acid solut cannot be injected into the body i producing severe necrosis, wherefore it is entirely unsuited for the treatment of varicosities. By comparisonl the product resulting from each of the processes hereinbefore described is both alkaline and holds the quinine permanently in a clear solution. When injected into; the veins, no necrosis occursas. hereinbefore stated, and so far as is known nosimilaralkaline solution has previously been produced; 'f Furthermore, it has also been discovered that instead. of using the free fatty acids of cod liver oil, the free fattyjacids of olive oil, oleic acid,

cotton seed oil, castor oil, and other vegetable andanimal oils, may be used with equal facility, and that allof the. known fatty acids will when heateddissolve-thequinine alkaloid and form' an oily solution. If such oily solution is poured into water andfsimultaneously stirred and heated, no separationlofthe quininealkaloidoccurs and the oily layers remain unchanged. If, however; norsodium hydroxide is added, the sodiuni. soap ofifthefattyacid. is formed, such for instance as sodium oleate or the sodium saltsof thejfatty acids of olive,'or of cotton seed, of. castor 'oil, or 3. of; vegetable orzanimaloils, each and all of which possesses thepropertyof maintaining the quinine alkaloid.- in colloidal solution.,. H

Fina1ly,.it-may be said in brief summary, that the sclerosing action of the sodium morrhuate and quinine in combination is greatly enhanced, over theuse. of: either of them independently-of the other, and that thisi inproved result is due to the new and original useof the sodium salts of the. fatty acid complex of animal and vegetable oilsrcombined with Cg uinine alkaloid. Furthermore, while the usepf. sodium. morrhuate alone produces reactionsin approximately three percent. (3%) of the many cases observed, and the independent use of quinine-hasasimilar effeet in about onepercent' (1%) of suchcases, the use of the two substancesin. one and the same solution does not produce the quinine reactions nor the sodium'morrhuate reaction sometimes. encountered. It seemsthat the alkaloidal quinine in colloidal dispersion in thesodium morrhuate (cod liver oil-.-soap) solution does not possess the. under irable properties of the crystalloid" quinine, which is contained intrue solutionsof qiiinine urea hydrochloride orquinine urethane.

'Havin'gnthus described my invention tvhat I ciaim. as new andv desire .to secure by Letters Patent, is:--- f f1. The process of producing a solution of qui--- ninealkaloid and:sodium morrhuate, which consistsin dissolving quinine alkaloid inamorrhuic acid, to producefquinine morrhtiate, and thendissolving the quinine morrhuatein normal so.-- dium. hydroxide. a

2. The process of producing a solution of quiof a vegetable or animal oil, which consists indissolving quinine alkaloid in the acid of a. vege table or animal oil, to produce quinine fatty acidacidcomplexes in normal sodium hydroxide.

3. The processiof. producing a solution of quinine alkaloid and sodium morrhuate; which consolving the quinine morrhuate in normal sodium hydroxide until the pH value is between 8 and 10 to produce a clear stable solution.

4. The process of producing a solution of quinine alkaloid and sodium salts of fatty acids, which consists in dissolving quinine alkaloid in the fatty acid of a vegetable or animal oil, to produce quinine fatty acid complexes, and then dissolving the quinine fatty acid complexes in normal sodium hydroxide until the pH value is between 8 and 10, to produce a clear stable solution.

5. The process of producing a. solution of quinine alkaloid and sodium morrhuate, which consists in dissolving quinine alkaloid in a. morrhuic acid to produce quinine morrhuate, adding benzyl alcohol, and finally adding normal sodium hydroxide until a pH value of 8 to 10 is reached, to produce a clear stable solution.

6. The process of producing a solution of quinine alkaloid and sodium salts of fatty acids, which consists in dissolving quinine alkaloid in the free fatty acid of a vegetable or animal oil, to produce quinine fatty acid complexes, adding benzyl alcohol and finally adding normal sodium hydroxide until a pH value of 8 to 10 is reached, to produce a clear and stable solution.

FREDERICK R. GREENBAUM.

CERTIFICATE GE CORRECTION.

Patent No 2,046,116. June 50, 1956.

FREDERICK R. GEEEEBAUM.

in the printed specification of on follows: Page 2, first the said Letters same may conform It is hereby certified that error appeafs the above ZUJIFUE-TBQ patent requiring correct column, 7 line 5 for the Word "table" read stable; and that Patent should be read with this correction therein that the to the record of the case in the Patent Office Signed and scaled this 22nd day of September,

Henry Van Arsdale (Seal) Acting Commissioner of Patents 

